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US4397839A Expired / Lapsed US ⏱️ 0.0 years remaining

Surface active material and process for preparing same

Assignee: TT Pharmaceuticals Inc
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Filing: 1982-03-04
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Granted: 1983-08-09
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Expires: 2002-03-04
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Abstract

Abstract A surface active material having the capacity of reducing the surface tension in pulmonary alveoli significantly is provided. This material comprises, based on the dry weight of the material, 68.6-90.7% of phospholipid, 0.3-13.0% of neutral fat, 0.0-8.0% of total cholesterol, 1.0-27.7% of free fatty acids, 0.1-2.0% of carbohydrate, and 0.0-3.5% of protein. The material is produced by subjecting mammalian lung tissue to a series of procedures including acetic acid ester treatment, organic solvent mixture treatment, differential centrifugation, density gradient centrifugation and dialysis, and optionally adding a phosphatidylcholine, a neutral fat, and/or a free fatty acid to the resulting product. A pharmaceutical composition comprising the surface active material is usable for the clinical treatment of respiratory distress syndrome.

Inventors

  • 👤 Yuji Tanaka

Bibliographic Details

Application Number —
Jurisdiction US
Data Source google_patents
Last Synchronized 2026-11-05 21:28
CPC Classifications
A; A61; A61K; A61K35/00; A61K35/12; A61K35/42; A61P; A61P11/00

Claims Analysis

Total Claims: 33
Claim 1
Independent Claim 162 words
A surface active material comprising (1) phospholipid, neutral fat, total cholesterol, free fatty acids, carbohydrate, protein and water, all of which are obtained from the lung tissue of a mammal, and (2) optionally at least one additional component selected from the group consisting of a phosphatidylcholine, a neutral fat and a free fatty acid, characterized in that the overall phospholipid content is 68.6-90.7%, the overall neutral fat content is 0.3-13.0%, the total cholesterol content is 0.0-8.0%, the overall free fatty acid content is 1.0-27.7%, the carbohydrate content is 0.1-2.0%, the protein content is 0.0-3.5%, and the water content is 2.1-5.2%, all based on the dry weight of the material, the surface tension of the material as measured at 15°-25° C. by Wilhelmy's method in which the material is added dropwise to the surface of physiological saline in an amount of 0.3-0.8 μg per square centimeter of the surface area thereof being 30.1-47.5 dynes/cm when the surface area is 54.0 cm 2 .
Claim 2
Dependent Claim 162 words
A surface active material comprising (1) phospholipid, neutral fat, total cholesterol, free fatty acids, carbohydrate, protein and water, all of which are obtained from the lung tissue of a mammal, and (2) optionally at least one additional component selected from the group consisting of a phosphatidylcholine, a neutral fat and a free fatty acid, characterized in that the overall phospholipid content is 68.6-90.7%, the overall neutral fat content is 0.3-13.0%, the total cholesterol content is 0.0-8.0%, the overall free fatty acid content is 1.0-27.7%, the carbohydrate content is 0.1-2.0%, the protein content is 0.0-3.5%, and the water content is 2.1-5.2%, all based on the dry weight of the material, the surface tension of the material as measured at 15°-25° C. by Wilhelmy's method in which the material is added dropwise to the surface of physiological saline in an amount of 0.3-0.8 μg per square centimeter of the surface area thereof being 30.1-47.5 dynes/cm when the surface area is 54.0 cm 2 .
Claim 3
Dependent Claim 100 words
A surface active material as claimed in claim 1 wherein the overall phospholipid content is estimated by multiplying its phosphorus content by 25; the overall neutral fat content is estimated by expressing its constituents in terms of mono-, di- and trioleoylglycerols and then calculating the sum total thereof; the total cholesterol content was estimated by expressing its constituents in terms of free cholesterol and cholesterol palmitate and then calculating the sum total thereof; and the overall free fatty acid content, the carbohydrate content and the protein content are expressed in terms of palmitic acid, glucose and bovine serum albumin, respectively.
Claim 4
Dependent Claim 32 words
A surface active material as claimed in claim 1 wherein the phospholipid consists essentially of, on a weight basis, 58.4-85.0% of phosphatidylcholine, 0.1-12.0% of phosphatidylglycerol, 3.5-12.6% of phosphatidylethanolamine, and 3.2-12.1% of sphingomyelin.
Claim 5
Dependent Claim 29 words
A surface active material as claimed in claim 3 wherein the content of phosphatidylcholine having two saturated fatty acid residues based on the total weight of phosphatidylcholine is 61.3-87.5%.
Claim 6
Dependent Claim 24 words
A surface active material as claimed in claim 1, 2, 3 or 4 wherein the phosphatidylcholine optionally used as an additional component is dipalmitoylphosphatidylcholine.
Claim 7
Dependent Claim 38 words
A surface active material as claimed in claim 1, 2, 3 or 4 wherein the neutral fat optionally used as an additional component is a member selected from the group consisting of tripalmitoylglycerol, tristearoylglycerol, trioleoylglycerol and mixtures thereof.
Claim 8
Dependent Claim 41 words
A surface active material as claimed in claim 1, 2, 3 or 4 wherein the fatty acid optionally used as an additional component is a member selected from the group consisting of palmitic acid, stearic acid, oleic acid and mixtures thereof.
Claim 9
Dependent Claim 28 words
A surface active material as claimed in claim 1, 2, 3 or 4 wherein the mammal is selected from the group consisting of cattle, horses, sheep and pigs.
Claim 10
Dependent Claim 32 words
A pharmaceutical composition useable for the treatment of respiratory distress syndrome comprising an effective amount of a surface active material as set forth in claim 1 and a pharmaceutically acceptable carrier thereof.
Claim 11
Dependent Claim 23 words
A pharmaceutical composition as claimed in claim 9 wherein the effective amount for adult patients is between 500 and 3,000 mg per treatment.
Claim 12
Dependent Claim 23 words
A pharmaceutical composition as claimed in claim 9 wherein the effective amount for premature infants is between 50 and 400 mg per treatment.
Claim 13
Dependent Claim 26 words
A pharmaceutical composition as claimed in claim 9, 10 or 11 wherein the carrier is selected from the group consisting of water and an electrolyte solution.
Claim 14
Dependent Claim 15 words
A pharmaceutical composition as claimed in claim 12 wherein the electrolyte solution is physiological saline.
Claim 15
Dependent Claim 27 words
A pharmaceutical composition as claimed in claim 9, 10 or 11 wherein the effective amount is administered directly into the airway of patients with respiratory distress syndrome.
Claim 16
Dependent Claim 20 words
A pharmaceutical composition as claimed in claim 14 wherein the effective amount is administered in the form of a suspension.
Claim 17
Independent Claim 391 words
A method of producing a surface active material comprising (1) phospholipid, neutral fat, total cholesterol, free fatty acids, carbohydrate, protein and water, all of which are obtained from the lung tissue of a mammal, and (2) optionally at least one additional component selected from the group consisting of a phosphatidylcholine, a neutral fat and a free fatty acid, characterized in that the overall phospholipid content is 68.6-90.7%, the overall neutral fat content is 0.3-13.0%, the total cholesterol content is 0.0-8.0%, the overall free fatty acid content is 1.0-27.7%, the carbohydrate content is 0.1-2.0%, the protein content is 0.0-3.5%, and the water content is 2.1-5.2%, all based on the dry weight of the material, the surface tension of the material as measured at 15°-25° C. by Wilhelmy's method in which the material is added dropwise to the surface of physiological saline in an amount of 0.3-0.8 μg per square centimeter of the surface area thereof being 30.1-47.5 dynes/cm when the surface area is 54.0 cm 2 , the method comprising the steps of: (a) bringing the minced lung tissue of a mammal into contact with an electrolyte solution to obtain an extract; (b) centrifuging the extract to collect a crude sediment; (c) adjusting the specific gravity of an aqueous suspension of the crude sediment by the addition of sodium chloride and centrifuging the adjusted suspension to isolate a top layer comprising an emulsified scum layer; (d) dialyzing an aqueous suspension of the top layer and lyophilizing the dialyzed suspension to obtain a crude dry product; (e) bringing the crude dry product into contact with an acetic acid ester to collect a material insoluble in the acetic acid ester and then bringing the insoluble material into contact with an organic solvent mixture to obtain a purified filtrate; and (f) concentrating the purified filtrate to obtain a solid residue, optionally adding to the solid residue at least one additional component selected from the group consisting of a phosphatidylcholine, a neutral fat and a free fatty acid, so as to provide an overall phospholipid content of 68.6-90.7%, an overall neutral fat content of 0.3-13.0%, and an overall free fatty acid content of 1.0-27.7%, all based on the dry weight of the final product, at well as an overall phosphatidylcholine content of 58.4-85.0% based on the total weight of phospholipid, and then lyophilizing the resulting mixture.
Claim 18
Independent Claim 391 words
A method of producing a surface active material comprising (1) phospholipid, neutral fat, total cholesterol, free fatty acids, carbohydrate, protein and water, all of which are obtained from the lung tissue of a mammal, and (2) optionally at least one additional component selected from the group consisting of a phosphatidylcholine, a neutral fat and a free fatty acid, characterized in that the overall phospholipid content is 68.6-90.7%, the overall neutral fat content is 0.3-13.0%, the total cholesterol content is 0.0-8.0%, the overall free fatty acid content is 1.0-27.7%, the carbohydrate content is 0.1-2.0%, the protein content is 0.0-3.5%, and the water content is 2.1-5.2%, all based on the dry weight of the material, the surface tension of the material as measured at 15°-25° C. by Wilhelmy's method in which the material is added dropwise to the surface of physiological saline in an amount of 0.3-0.8 μg per square centimeter of the surface area thereof being 30.1-47.5 dynes/cm when the surface area is 54.0 cm 2 , the method comprising the steps of: (a) bringing the minced lung tissue of a mammal into contact with an electrolyte solution to obtain an extract; (b) centrifuging the extract to collect a crude sediment; (c) adjusting the specific gravity of an aqueous suspension of the crude sediment by the addition of sodium chloride and centrifuging the adjusted suspension to isolate a top layer comprising an emulsified scum layer; (d) dialyzing an aqueous suspension of the top layer and lyophilizing the dialyzed suspension to obtain a crude dry product; (e) bringing the crude dry product into contact with an acetic acid ester to collect a material insoluble in the acetic acid ester and then bringing the insoluble material into contact with an organic solvent mixture to obtain a purified filtrate; and (f) concentrating the purified filtrate to obtain a solid residue, optionally adding to the solid residue at least one additional component selected from the group consisting of a phosphatidylcholine, a neutral fat and a free fatty acid, so as to provide an overall phospholipid content of 68.6-90.7%, an overall neutral fat content of 0.3-13.0%, and an overall free fatty acid content of 1.0-27.7%, all based on the dry weight of the final product, at well as an overall phosphatidylcholine content of 58.4-85.0% based on the total weight of phospholipid, and then lyophilizing the resulting mixture.
Claim 19
Dependent Claim 21 words
A method as claimed in claim 16 wherein the lung tissue minced with a meat grinder is used in step (a).
Claim 20
Dependent Claim 18 words
A method as claimed in claim 16 wherein the electrolyte solution used in step (a) is physiological saline.
Claim 21
Dependent Claim 26 words
A method as claimed in claim 16 wherein, in step (c), the specific gravity of the aqueous suspension of the crude sediment is adjusted to 1.10-1.20.
Claim 22
Dependent Claim 24 words
A method as claimed in claim 16 wherein, in step (d), the aqueous suspension of the top layer is dialyzed through a cellophane membrane.
Claim 23
Dependent Claim 36 words
A method as claimed in claim 16 wherein, in step (e), 1 part of the crude dry material is suspended in 20-200 parts of the acetic acid ester at a temperature of -10° to 10° C.
Claim 24
Dependent Claim 28 words
A method as claimed in claim 21 wherein the acetic acid ester is selected from the group consisting of methyl acetate, ethyl acetate, propyl acetate and butyl acetate.
Claim 25
Dependent Claim 32 words
A method as claimed in claim 16 wherein, in step (e), 1 part of the material insoluble in the acetic acid ester is suspended in 20-200 parts of the mixed organic solvent.
Claim 26
Dependent Claim 48 words
A method as claimed in claim 23 wherein the organic solvent mixture is selected from the group consisting of chloroform-methanol with a volume ratio of 2:1, chloroform-ethanol with a volume ratio of 2:1, chloroform-isopropanol with a volume ratio of 2:1, and ether-ethanol with a volume ratio of 1:3.
Claim 27
Dependent Claim 21 words
A method as claimed in claim 16 wherein, in step (f), the phosphatidylcholine optionally added to the solid residue is dipalmitoylphosphatidylcholine.
Claim 28
Dependent Claim 35 words
A method as claimed in claim 16 wherein, in step (f), the neutral fat optionally added to the solid residue is a member selected from the group consisting of tripalmitoylglycerol, tristearoylglycerol, trioleoylglycerol and mixtures thereof.
Claim 29
Dependent Claim 39 words
A method as claimed in claim 16 wherein, in step (f), the free fatty acid optionally added to the solid residue is a member selected from the group consisting of palmitic acid, stearic acid, oleic acid and mixtures thereof.
Claim 30
Dependent Claim 31 words
A method as claimed in claim 16 wherein the centrifugation of step (b) is carried out at 8,000-20,000 r.p.m. and the centrifugation of step (c) is carried out at 5,000-13,000 r.p.m.
Claim 31
Dependent Claim 26 words
A method as claimed in claim 16 wherein the mammal used in step (a) is selected from the group consisting of cattle, horses, sheep and pigs.
Claim 32
Dependent Claim 14 words
A method as claimed in claim 29 wherein 0- to 4-months-old calves are used.
Claim 33
Dependent Claim 13 words
A method as claimed in claim 29 wherein 3-months-old young pigs are used.

References Cited (Backward Citations)

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USPTO Annuity & Maintenance Windows

Annuity Stage Window Opens Payment Deadline Surcharge Period Until Estimated Fee Status
3.5 Years (Year 4) 1986-08-08 1987-02-07 1987-08-09 $2000.00 Window Closed / Lapsed
7.5 Years (Year 8) 1990-08-08 1991-02-07 1991-08-09 $3760.00 Window Closed / Lapsed
11.5 Years (Year 12) 1994-08-08 1995-02-07 1995-08-09 $7700.00 Window Closed / Lapsed

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